Abstract The dual epidemics of obesity and type 2 diabetes are among the most important challenges to improving health in the United States. The staggering human and monetary costs of these disorders are the direct result of not having treatments that can be delivered to the large number of patients in need. Interestingly, it is not because we don?t have effective treatment options. Bariatric surgical procedures provide sustained weight loss of more than 30%; much greater than can be achieved with lifestyle or current pharmacological treatments. Moreover, some of these procedures provide for substantial reductions in severity or outright remission of type 2 diabetes. However, given the high cost, risk and invasiveness of surgery, it simply is not an appropriate solution for the millions of individuals suffering with obesity and/or type 2 diabetes. While the clinical effectiveness of these procedures has become more widely appreciated, we still understand precious little about the underlying mechanisms that produce these benefits. At first blush, it would seem obvious as to how these procedures produce their effects; i.e., they are restrictive (making a smaller stomach), malabsorptive (reducing the number of calories absorbed from ingested food), or both. However, many lines of evidence have undermined these simple explanations and point to a much richer set of possibilities. We have focused our attention on a procedure termed Vertical Sleeve Gastrectomy (VSG), a procedure in which 80% of the greater curvature of the stomach is removed, reducing the remaining stomach to a tube or ?sleeve?. We have generated several lines of evidence that the ability of VSG to reduce weight and improve glucose regulation depends on changes on the levels and actions of bile acids via the nuclear bile-acid receptor, FXR. One specific goal of this proposal is understand how VSG alters levels of bile acids by infusing labelled bile acids and determining their fate in rodents with or without VSG. A second goal is to test several hypotheses directed at uncovering the key populations of FXR and the FXR-target genes that mediate the diverse effects of VSG. To do so, we will use Cre-LoxP approaches to selectively knock down expression of FXR in liver or intestine and test the effectiveness of VSG to improve a large number of metabolic variables. Identifying the molecular mechanisms by which surgery exerts these effects is an important research goal that has direct clinical implications. By identifying the key molecular underpinnings of bariatric procedures, we can harness the benefits of surgery while lowering cost and invasiveness. This research can improve surgical treatment of obesity and diabetes while we also identify new treatment strategies that would make surgical treatment obsolete.